Substituted methylene steroids and their preparation



US. Cl. 260-69745 2 Claims ABSTRACT OF THE DISCLOSURE The presentinvention relates to novel 16,17-(substitutedmethylene)-l1,20-oxygenated steroids of the pregnane series exertingstrong glucocorticoid, anti-inflammatory, progestational,anti-uterotrophic, ovulation-inhibiting and pregnancy-maintainingproperties, and to a process for the preparation thereof.

This invention relates to novel 16a,17a-methylene steroids, in which themethylene group is substituted, and to a process for their preparation.

More particularly, it relates to novel 16a,17cc-(SubSti tutedmethylene)-steroids of the pregnane series having the partial formula:

wherein R =H, OH, OAcyl or halogen,

X i=hydrogen or a saturated or unsaturated hydrocarbon,

X =saturated or unsaturated hydrocarbon, or

X +X =together with the methylene carbon atom a saturated or unsaturatedcycloaliphatic radical.

The present invention particularly comprises the novel compounds havingthe formula:

wherein C -C and/ or C -C may be a single or double bond, Y H(OH),H(OAcyl) or O,

W=H or halogen,

Zr H, CH or halogen, and

R X and X have the meanings as defined above.

The compounds according to the invention are very valuable on account oftheir biological activities. They exert strong glucocorticoid,anti-inflammatory, progestational, anti-uterotrophic,ovulation-inhibiting and pregnancy-maintaining activities.

The compounds according to the invention may be administeredparenterally or orally in the form of sus United States Patent icepensions, solutions, emulsions or solid pharmaceutical dosage unitforms, usually after mixing with auxiliaries, or, if desired, with otheractive components.

16,l7-methylene-steroids, in which the methylene group is notsubstituted, are known. They are obtained as byproduct in extremely lowyields by subjecting the corresponding 16,17-pyrazolino compounds tothermal treatment, a process which leads principally to 16-methyl-Asteroids, or in better yield by treatment with an acid catalyst.

Surprisingly, it has now been found that 16,17-(substitutedmethylene)-steroids as defined above can be obtained from thesubstituted pyrazolino-steroids in good yield by thermal treatment or byphotolysis with only trace amounts of the A -compounds being formed asbyproducts. Treatment of the pyrazolino-steroids with an acid catalystrather surprisingly gives lower yields of the substituted methylenecompounds from the substituted pyrazolino steroids.

The reaction may be illustrated by the following reaction scheme.

wherein X and X have the meanings as defined above.

The 16,17-(substituted-pyrazolino)-steroids can be obtained by thereaction of a suitable A -20-keto-ster0id with the appropriatediazo-compound of the formula X X C-N This reaction is usually carriedout in a suitable organic solvent such as an ether or a halogenatedhydrocarbon, and at a temperature preferably below C.

The conversion of the thus obtained16,17-(substitutedpyrazolino)-20keto-steroids into the corresponding16,17- (substituted-methylene)-20-keto-steroids by splitting off ofnitrogen may be performed by thermal treatment, by photolysis, or lessefiectively by treatment with an acid catalyst.

The thermal treatment is usually carried out at a temperature between100 C. and 225 C. either alone at atmospheric or reduced pressure, or inan inert solvent such as Decalin or toluene until one molecularequivalent of nitrogen has been liberated, usually 15 to minutes.

The photolysis is normally carried out by irradiating a solution of the16,17-(substituted-pyrazolino)-steroid in a suitable solvent, such asdioxan, by means of a medium or high pressure mercury vapour lamp placedat a suitable distance from the reaction flask, which is preferably ofquartz.

The splitting off of nitrogen may also be accomplished by treating thesubstituted diazomethylene compound with an acid catalyst, such as aLewis acid like boron trifluoride, or its etherate, or an organic orinorganic acid such as perchloric acid, trifluoro acetic acid and thelike. Usually the reaction is performed in such a way that thesubstituted diazomethylene compound is added to a solution of the acidcatalyst used in a suitable organic solvent, which may be an ether, e.g.dioxane, an aliphatic ketone, such as acetone, or a halogenatedhydrocarbon, such as methylene chloride. A preferred method consists ofreacting the substituted diazomethylene compound with a combination ofboron trifluoride or its etherate, a solvent and a surface-activecatalyst which may be the diazomethylene compound iteslf. The acidcatalyst treatment is preferably carried out at a temperature between C.and 50 C., usually at about 20 C.; the reaction time varies betweenminutes and some hours according to the temperature of the reaction.

The A --keto-pregnene compounds to be used as starting products may be A-3-keto, A -3-hydroxy-, A -3- acyloxy-, or 3-oxygenerated ring Asaturated pregnane compounds which may be substituted in 6-, 9- and/orll-positions in addition to the 2l-position, but it is also possible tointroduce these substituents after the introduction of the16a,17u-substituted methylene group.

In the 16,17-(substituted methylene) steroids herein described, groupsalready present may be modified and other groups or functions may beintroduced. For example, acyloxy groups may be hydrolysed to thecorresponding hydroxy compound. Hydroxy groups, in particular the 3-hydroxy group may be oxidised, e.g. by Oppenauer oxidation, in the caseof the 3-hydroxy-A -steroids leading to 3-keto-A -steroids, andadditional double bonds may be introduced by known chemical ormicrobiological means. Thus a 3-keto-5 ,8-steroid may be converted to a3-keto- A -steroid by means of selenium dioxide or by bromina tion anddehydrobromination. A 3-keto-5a-steroid or a 3-keto-A -steroids may beconverted into a 3-keto-A steroid by means of selenium dioxide ordichloro-dicyano rquinone (D.D.Q.); a 3-keto-A -steroid may be convertedinto a corresponding A -dehydro derivative by a suitable quinone havinga redox potential less than 0.5 such as tetrachloroquinone (chloranil).

The microbiological introduction of a double bond at position 1 may becarried out by incubation with, for example Bacillus sphaericus orCorynebacterium simplex.

In a 3-keto-5a-steroid it may also be possible to introduce double bondsat position 1 and 4 simultaneously by halogenation and subsequentdehydrohalogenation.

Halogenation in position 21 may be carried out in a manner known per see.g. the 20-keto-pregnane derivative is treated with iodine and in asolvent such as methanol in the presence of an alkaline substance suchas sodium hydroxide or calcium oxide. The 21-fluoro compounds may beobtained from the corresponding 21-iodo compounds by treatment withsilver fluoride in acetonitrile.

21-acetoxy derivatives may be obtained by treatment of the 21-iodo or21-bromo-derivative with, for example, silver acetate in pyridine. Afterhydrolysis the resultant 21-hydroxyl group may be resterified with aninorganic acid such as sulphuric acid or with a monoor poly-carboxylicacid preferably having 1 to 18 carbon atoms in a known manner.

Introduction of an ll-hydroxyl group may be performed microbiologicallye.g. with the aid of a micro-organism such as a Curvularia or a Rhizopusafter which it may be acylated or oxidized. The 9oc-bromo-11B hydroxycompounds may be obtained from the A -compounds by treatment withhypobromous acid which may be prepared in a manner per se fromN-bromosuccinimide. The 9w fluoro-llp-hydroxy compound may be preparedby treating the 9a-bromo-115-hydroxy compound with base and reacting theresultant 913,11fl-oxide with hydrofluoric acid.

The invention is further illustrated by the following examples.

EXAMPLE I A solution of ethyl-N-nitroso-N-allyl carbamate (80 g., 0.51mole) in ether (300 ml.) was treated with 20% methanolic potassiumhydroxide ml.) dropwise with cooling. The etheral solution ofdiazopropene (0.25 mole) was washed with water until neutral and thenadded to a solution of pregnene-3B,l1a-diol-20-one diacetate (11 g.) inether (100 m1.) and methanol (300 ml). After standing for 18 hours thesolution was concentrated under reduced pressure and the 1611,17a-vinylpyrazolinopregnane- 3,8,l1a-dio1-20-one diacetate whichcrystallised out was collected and recrystallised from methanol (6.2g.).

16u,17a-[3',1',-(3-vinyl 1 pyrazolino] 5oz pregnane-3fl,l1o-dioldiacetate (300 mg.) was heated in vacuo at 190 -200 C. until evolutionof nitrogen has ceased (45 mins.). The resulting oil was crystallisedfrom ethyl acetate to give 16ot,17 x-(l'-vinyl-methylene(-5a-pregnane-3fi,llot-diol-20-one diacetate (160 mg.) M.P. 116-1 19 C.

A solution of 16a,17u-vinylpyrazolinopregnane 35, lloc-diOl-ZO-Ollediacetate (5 g.) in toluene (25 ml.) was boiled under reflux in anatmosphere of nitrogen for 30 mins., and then distilled to dryness underreduced pressure. The residue was dissolved in methanol and allowed tocrystallise when 16a,17u-vinylmethylenepregnane-3p,11a-dio1-20-diacetate (3.4 g.) was obtained. Hydrolysis in 5% methanolicpotassium hydroxide solution gave the free 3,8,11-diod.

16a,l7a-vinylmethylenepregnane 3,3,ll-rx diol-ZO-one (2. g.) wasdissolved in acetone (30 ml.), cooled and treated with a solution ofchromic acid (1 g.) in water (1 ml.) and acetone (10 ml). After beingstirred for 2 hours the solution was diluted with water and the crudetrione filtered 01f. Recrystallisation from aqueous methanol gave16a,l7u-vinyl-methylene-pregnane 3,11,20- trione (1.5 g.).

161a,l7a-vinylmethylenepregnane 3,11,20 trione (l g.) in toluene (40ml.) was boiled under reflux for 18 hours with D.D.Q. (1.1 g.). Aftercooling the quinol was filtered oil and the solution run through a 3column of alumina, distilled to dryness under reduced pressure and theresidue crystallised from methanol to give pure 16a,17a-vinylmethylenepregn 1,4 diene 3,11,20 trione (0.6 g.).

EXAMPLE II A solution of pregna-4,l6-dien-11fi-ol-3,20-dione (5 g.) inether (50 ml.) and methanol ml.) was treated with a solution ofdiazopropene prepared according to Example I (from 40 g.ethyl-N-nitro-allyl-carbamate). After standing at room temperature for24 hours, the solution was concentrated under reduced pressure and theresidual solution allowed to crystallise. The crystals were collectedand recrystallised from methanol to give 17a [3,1' (3vinyl-1'-pyrazolino)]-pregn-4-en-1lflol-3,20-dione (3.1 g.).

The foregoing pyrazolino compound (2 g.) was dissolved in toluene (15ml.) and boiled under reflux for 45 mins. under an atmosphere ofnitrogen and then distilled to dryness under reduced pressure.16oz,17oc(1' vinylmethylene) pregn 4 en-1lfi-ol-3,20'dione was obtainedby crystallising the residue from methanol.

In a similar manner 6lX-II1Cfl1y1-6d-Ch1OI'O-, 6a--fluoro-,604,9ot-difil101'0- and Qa-fluoro pregn 4,16 dien-llfiol-3,20-dione werecondensed with diazo-propene to give the corresponding 16a,17oL-[3',1'(3'-vinyl 1' pyrazolino)] compounds.

Pyrolysis of these pyrazolino compounds in boiling toluene as describedin Example I yielded the 6ot-rnethyl, 60cchloro, 6a-fll10IO-,60,9ot-difill0l0- and 9a-fluoro-16a,17u- (1-vinylmethylene)-pregn 4 en11,8 ol-3,20-diones, after crystallisation from methanol.

EXAMPLE III A solution of l6u,17a-(1'-vinylmethylene)-pregn-4-en-1lfl-ol-3,20-dione (2.5 g.) and chloranil (2.5 g.) in tbutanol (100 ml.)was boiled under reflux for one hour and concentrated under reducedpressure. The residue was extracted with methylene chloride, filtered,washed with 2 N sodium hydroxide solution and then water until neutral.The methylene chloride solution was then run through a column of alumina(20 g.) and washed through with more methylene chloride. The solutionwas then evaporated to dryness and the residue crystallised frommethanol to give 16a,-17tx-(1'-vinylmethylene)-pregna- 4,6-dien-1 1[3-016 ,20-dione.

In an analogous manner 6a-methyl, 6oz-ChlOIO-, 6a-fluoro-,6a,9u-difluoroand9a-fluoro-16a,17u-(1'-vinylmethylene)-pregn-4-en-11B-ol-3,20-dione wereconverted into the A -pregnadiene derivatives.

EXAMPLE IV A solution of 16a,17a-(1-vinylmethylene)-pregn-4-en-11,8-ol-3,20-dione (2.5 g.) in benzene (50 ml.) was boiled underreflux with D.D.Q. (2.5 g.) for 16 hours, cooled, filtered, washed with2N sodium hydroxide solution and then water. After drying the benzenesolution was passed down a column of alumina (100 g.) and then distilledto dryness under reduced pressure. The residue crystallised frommethanol to give16ot-17tx-(1'-vinylmethylene)-pregna-1,4-diene-11,8-01-3 ,20-dione.

In a similar manner 6a-methyl, 6ot-chloro-, 6cx-fluoro, 6a,9a-difluoroand 9a-fluoro-16a,17a-(1-vinylmethylene)-pregn-4-en-1l/i-ol-3,20-dionewere converted into the corresponding n -pregna-diene derivatives.

EXAMPLE V A solution of 16a,17u-(1-vinylmethylene)-pregn-4,6-dien-11B-ol-3,20-dione (1 g.) and D.D.Q. (1 g.) in benzene (20 ml.) wasboiled under reflux for 16 hours, cooled and filtered. The filtrate waswashed with N sodium hydroxide solution and then water, dried anddistilled to dryness under reduced pressure. The residue aftercrystallisation from methanol yielded 16a,17a-(1- vinylmethylene)-pregna-1,4.,6-triene-1 13-01-3 ,ZO-dione.

In a similar manner 6a-methyl-, 6a-chloro-, 6a-fluoro-,606,90t-dlfl1101'0 and9u-fluoro-16tx,l7a-(1-vinylmethylene)-pregna-4,6-dien-11,8-l-3,20-dionehave been converted into the corresponding A -pregnatriene derivatives.

EXAMPLE VI A solution of ethyl-N-nitroso-propargylcarbamate g.) in ether(10 ml.) was treated with methanolic potassium hydroxide (5 ml.)dropwise with ice cooling. The ethereal solution of diazo propene thusformed was washed with water until neutral and then added to a solutionof pregn-4,16-dien-l1fl-ol-3,20-dione (2.5 g.) in ether ml.) andmethanol (80 ml.). After standing at 5-10 C. for 2 days, the solutionwas concentrated to 20 ml. under reduced pressure and the solution setaside at 0-2 C. for 2 days to allow the product to crystallise. Theproduct was filtered off and recrystallised from methanol to give16a,17a-[3'-1'-(3-ethylnyl-1-pyrazolino)]pregn- 4-en-11B-ol-3,20-dione.

In a similar manner the 6a-methyl-, 6a-chlor0-, 6afluoro-,60:,9a-difll1010- and 9a-fluoro derivatives of 161x,- 17a-[3,1-(3-ethynyl-1-pyrazolino)]-pregn 4 enl1fl-ol-3,20-dione were prepared.

EXAMPLE VII (a) A 2% solution of16a,17a-[3,1-ethynyl-1-pyrazolino)]-pregn-4-en-11fl-ol-3,20-dione (1 g.)in dioxan was irradiated in a quartz flask by means of a medium pressuremercury vapour lamp set 6 cm. way for mins. The solution was thenevaporated to dryness under reduced pressure and the residuecrystallised from methanol to give 16a,17ot-(l-ethynylmethylene)-pregn-4-en-11(3- ol-3,20 -dione.

(b) A solution ofl6a,17o-[3',1-(3-ethynyl-1-pyrazolino)]-pregn-4-en-11fl-ol-3,20 dione (2g.) in toluene (15 ml.) was boiled under reflux for 45 mins. and thendistilled to dryness under reduced pressure. Crystallisation of theresidue from methanol yielded 16a,17a-(l-ethynyl methylene)-pregn-4-en-1 15-01-3 ,ZO-dione.

In an analogous way the L-II1thyl-, 6a-chloro-,6afluoro-,6a,9a-difluoroand 9a-fluoro-derivatives of 160:,-17(X-[3',1',-( 3 -ethynyl-1-pyrazolino) ]-pregn-4-en-1 1,8-01-3,20-dione have been converted into the corresponding 616u,17a-(l'-ethynyl methylene) pregn4-en-l1;3-ol-3,20- dione analogues.

EXAMPLE VIII Pregna-4,16-dien-11/8-ol-3,20-dione (5 g.) in ether (50ml.) and methanol ml.) was treated with a solution of diazo-ethaneprepared from nitrosoethylurea (20 g.). The solution was left at roomtemperature in the dark for two days and the solvent then removed bydistillation under reduced pressure. The residue was crystallised frommethanol to give 16a,l7a [3,1(3'-methyl-1'-pyrazolino)]-pregn-4-en-11fl-ol-3,20-dione (3.3 g.).

A solution of l6ot,l7oc [3,1(3-methyl-1-pyrazolino)]-pregn-4-en-1lfi-ol-3,20-dione (2.0 g.) inacetone (50 ml.) was treated with boron trifiuoride (2 ml.) and a fewcarborundum chips. After two hours at room temperature the solution waswarmed to complete liberation of nitrogen. The solution was poured intodilute sodium bicarbonate solution and the precipitate collected. Aftercrystallisation from acetone-methanol there was obtained16a,17ot-(1'-methylmethylene)-pregn-4-en 11fi-ol.-3,20- dione.

In an analogous manner pregna-4,16-dien-115-01-320- dione has beencondensed with l-diazopropane, 2-diazopropane, diazo-nbutane,diazocyclopropane and phenyldiazomethane to give the corresponding16a,17txpyrazolino compounds substituted in the methylene group by 3-ethyl-, 3',3'-dimethyl- 3-n-propyl-, 3,3-spirocyclopropyl-, and 3-phenylrespectively.

Treatment of these substituted pyrazolino compounds with borontrifiuoride etherate as described above yielded16a,17a-(1-ethy1methy1ene)-, 1604,1711 (1,1 dimethyl methylene-,16a,l7a-(1'n-propyl methylene)-, 16ot,l7ot- (1,1-spirocyclomethylene)and 16u,17a (1-phenvl methylene) -pregn-4-en-l 1,8-ol-3,20-dionerespectively.

EXAMPLE IX In the manner described under Example VIII Qa-HUOIO-pregna4,l6-dien-1lB-0l-3,20-di0ne was condensed with diazo-ethane,l-diazopropane, 2-diazopropane, diazo-nbutane, diazocyclopropane andphenyldiazomethane to give the 16a,17 x-(3',1'-pyrazolino)-compoundssubstituted in the methylene group by 3'-methyl-, 3-ethyl-, 3,3'dimethyl, 3'-n-propyl-, 3,3' spirocyclopropyl and 3'- phenylrespectively.

Treatment of these l6u,17a-(3,1-pyrazolino)-compounds in the mannerdescribed yielded the 16a,17a-(1- methyl methylene)-,l6tx,l7a-(1-ethyl-methylene)-, a, a (1,l dimethyl methylene)-,16a,17a-(1-n-propylmethylene)-, 16a,l7o (1' spirocyclopropyl methylene)-and 16a,17a-(1-phenyl methylene)-pregn-4-en-l1fl-ol-3, 20-dionerespectively.

In a similar manner 6a-methyl-, 6a-chloro-, 6a-fiuoroand 6u,9udifluoro-pregn 4,16 dien-11fi-ol-3,20'dione have been condensed withdiazo-ethane, l-diazopropane, Z-diazopropane, diazo-n-butane,diazocyclopropane and phenyldiazomethane to give the correspondingsubstituted pyrazolino compounds.

Splitting off of nitrogen with boron trifiuoride etherate in the mannerdescribed gave the 16a,17a-methylenepregn-4-en-11,8-0l-3,20-dionederivative substituted in the 1611,1706-11'1CthY16I16 group by eithermethyl, ethyl, dimethyl, n-propyl, spirocyclopropyl or phenyl and in thenucleur by 6a-methyl-, 6oc-Chl01O-, 6a-fluoro or 6u,9adifluoro.

EXAMPLE X Pregna-4,9(1l),16 trien 21-ol-3,20-dione acetate (15 g.) inmethanol (100 ml.) and methylene chloride (100 ml.) was distilled underreduced pressure to remove the greater part of the methylene chlorideand a solution of diazopropene (prepared from 40 g. of nitrosoallylurea)in ether (600 ml.) and methanol (100 ml.) added. After 4 days at 3 C.the methylene chloride and ether were distilled off under reducedpressure and the crude pyrazolino compound filtered off and crystallisedfrom methanol to give pure 16a,17a-(3-vinyl-1'-pyrazolino)-pregna-4,9(11) dien 21-0l-3,20-dione acetate. Pyrolysis of this pyrazolinocompound as described under Example I yielded 1611,17 (1'vinylmethylene) pregna-4,9(11)- dien-2l-ol-3,20-dione acetate.

In a similar manner 6a-fiuoro-pregn-4,9(11),16-trien- 21-ol-3,20-dioneacetate was converted via the pyrazolino compound into 6oc-fl110r016oc,17oc (1'-vinylmethylene)- pregna-4,9(11)-dien-21-ol-3,20-dioneacetate.

EXAMPLE XI Pregna-4,l6-dien-21-ol 3,11,20 trione acetate andpregna-4,16-diene-1lfi,2l-diol-3,20-dione 21 acetate were converted intothe corresponding 3-vinyl-1-pyrazo-lino compounds as described underExample 1. The resultant pyrazolino compounds were irradiated in aquartz flask in dioxan (2% solution) by means of a medium pressuremercury vapour lamp placed 6 cm. away for 45 mins. After removal of thedioxan by distillation under reduced pressure the residues werecrystallised from methanol to yield16u,17a-(1-vinylmethylene)-pregn-4-en-21-ol-3,11, 20-trione acetate and16oz,17a-(l'-vinylmethylene)-pregn- 4-en-1l/3,21-diol-3,20-dione 21acetate.

EXAMPLE XII 6a-methyl-, 6OL-ChlOTO-, 6u-fluoro, 6a,9a-difluoroand 9afluoro pregn 4,16 dien-l1B,21-diol-3,20-dione 2lacetate were convertedinto the corresponding 3-vinyl-1'- pyrazolino compounds as describedunder Example I. Pyrolysis of these pyrazolino compounds at 185-195 C.gave products which after crystallisation from methanol yielded6a-methyl-, 6a-chloro-, 6oc-fll10fO-, 6a,9a-difluoroand 9a-fluoro16ot,l7oz (1'-vinylmethylene)-pregn-4-en- 11fl,21-diol-3,20-dione21-acetate respectively.

EXAMPLE XIII A solution of 160:,17a-(1-vinylmethylene)-pregn-4-en-11fl,21-diol-3,20-dione 21-acetate (2.5 g.) and chloranil (2.5 g.) int-butyl alcohol (100 ml.) was refluxed for one hour and thenconcentrated under reduced pressure. The residue was dissolved inmethylene chloride, filtered and then washed with 2 N sodium hydroxidesolution and then with water until neutral. The solution was then passeddown a column of alumino (20 g.), the eluate evaporated and the residuecrystallised to give 16a,17a- (1' vinylmethylene)preg.na-4,6-dien-llfi,21-diol-3,20- dione 21-acetate.

In an analogous manner 6a-methyl-, 6a-Chl0I'O-, 6afluoro-,6oz,9a-difluoroand 9a-fil1OIO-16a,17a-( l'-vinylmethylene)pregn-4-en-l1,8,21-diol-3,20dione 21-acetate were converted into thecorresponding A -pregna-diene derivatives.

EXAMPLE XIV A solution of 16a,17a-(l'-vinylmethylene)-pregn-4-en-1l;8,21-diol-3,20-dione 21-acetate (2.5 g.) and D.D.Q. (2.5 g.) indioxan (50 ml.) was refluxed for 16 hours, cooled and filtered. Thefiltrate was concentrated under reduced pressure and then diluted withmethylene chloride. The solution was then washed with dilute sodiumcarbonate solution and water, dried over sodium sulphate and evaporatedto dryness. The residue was passed down alumina (50 g.) inbenzene-petrol (60/80) 2:1 solution. The product recovered by removal ofthe benzene-petrol was recrystallised from acetone/ methanol to give16oz,17a- (1' vinylmethylene) pregna 1,4-dien-11,8,21-diol-3,20- dione21-acetate (1.5 g.).

In a similar manner 6a-methyl-, 6a-chloro-, 6afll101'O-,606,90t-dlfllll0- and 9a-fluoro 16oc,17ot (1'-vinylmethylene) pregn4-en-1lfi,21-diol-3,20-dione 21-acetate were converted into thecorresponding A -pregnadiene derivatives.

EXAMPLE XV A solution of 16a,17a-(1'-vinylmethylene)-pregna-4,6-dien-llp,21-diol-3,20-dione 21-acetate (1 g.) and D.D.Q.

Cir

(1 g.) in benzene (20 ml.) was boiled under reflux for ten hours, cooledand filtered. The filtrate was evaporated under reduced pressure and theresidue dissolved in benzene, washed with 2 N sodium hydroxide solutionand then with Water until neutral, dried over sodium sulphate and passeddown a column of alumina (50 g.). The benzene eluate was distilled todryness under reduced pressure and the residue crystallised frommethanol to give a,

I 17a (1' vinylmethylene)-pregna-1,4,6-trien-1 15,21-diol- 3,20-dioneZI-acetate.

In an analogous manner 6a-methyl-, 6ot-chloro-, 60L- fiuoro-, and9u-fluoro-l6ot,l7ot-(1-vinylmethylene)-pregna-1,4-dien-1lfi,2l-diOl-3,20di0ne21-acetate were converted to the corresponding A -pregnatrienederivatives.

EXAMPLE XVI Hydrolysis of the 16a,17ot-(1-vinylmethylene)-20-keto-21-acetoxy-pregnane derivatives described in Examples II to IX to thecorresponding free 21-hydroxy derivatives was carried out by dissolvingthe steroid in a saturated solution of potassium bicarbonate in methanol(40 vols.) under nitrogen and stirring at room temperature for one hour.The solution was neutralised with acetic acid, concentrated underreduced pressure and the product precipitated by addition of water.

Re-esterification was carried out by dissolving the 21- hydroxy steroidin two parts of pyridine and adding (1) the appropriate anhydride (2moles) or (2) the appropriate acid chloride (1.5 moles), allowing tostand at room temperature for 18 hours and decomposing by the slowaddition of water with stirring. The esters were extracted withmethylene chloride, washed with dilute alkali and then water, evaporatedto dryness and recrystallised.

The following 2l-esters were prepared: Propionate, pivalatefl-phenylpropionate, decanoate, hydrogen succinate.

EXAMPLE XVII Pregna-4,16-diene-11fi,21-diol-3,20-dione 21-acetate (15g.) in methylene chloride (100 ml.) and methanol (100 ml.) was treatedwith a solution of diazopropyne (prepared from 40 g. ofnitrosopropargylurea) and allowed to stand 4 days at 05 C. The solutionwas then concentrated to about 40 ml. under reduced pressure and theproduct allowed to crystallise. The crude product was recrystallisedfrom methanol to give pure 16oc,l7oc-(3'- ethynyl1-pyrazolino)-pregn-4-ene-11fi,21-diol-3,20-one 21-acetate.

Pyrolysis of this pyrazolino compound at -190 C. in vacuo for 25 mins.followed by chromatographic purification in benzene-hexane 2:1 yielded16u,17a-(l'-ethynylmethylene)-pregn-4-en-1 lp,21-diol-3,20-dione21-acetate.

In a similar manner 6a-methyl-, 6a-chloro-, 6a-fluoroand 91x fluoropregna-4,16-diene-11,8,21-diol-3,20-dione 21-acetate were condensed withdiazopropyne to give the corresponding 3 ',1'- (3'-ethynyl-methylene-1-pyrazolino) compounds. These pyrazolino compoundson pyrolysis yielded the corresponding 6u-methyl-, -6u-chloro-,6afluoroand 9m fluoro 16u,17 x-(1'-ethynyl-methylene)-pregn-4-en-11p,21-dione 21-acetate respectively.

EXAMPLE XVIII Pregna-4,16-diene-11;8,21-di0l-3,20 dione 21-acetate (5g.) in methylene chloride (50 ml.) and methanol (50 ml.) was treatedwith an etheral solution of diazoethane prepared from nitrosoethylurea(40 g.). The solution was kept at 0-5 C. for 4 days and thenconcentrated under reduced pressure to about 20 ml. and set aside at 05C. to crystallise. The solid was filtered ofl? and recrystallised frommethanol to give pure 16oz,17oc-3',l'-(3'-mthyl- 1' pyrazolino) pregn4-en-1lfl,21-diol-3,20-dione 21- acetate (4.8 g.).

The pyrazolino compound (2 g.) was photolysed in dioxan (200 ml.) for 45mins., evaporated under reduced pressure and the residue crystallisedfrom methanol to 9 give 16a,17 (1'-methylmethylene)-pregn-4-en-115,21-diol-3,20-dione 21-acetate (1.2 g.).

In an analogous manner pregna-4,16-diene-1 15,21-dio1- 3,20-dione21-acetate was condensed with l-diazopropane, 2-diazopropane,diazo-n-butane, diazo-cyclopropane and phenyl-diazo methane to give thecorresponding pyrazolino compounds substituted in the methylene groupwith ethyl, dimethyl, n-propyl, spiro-cyclo-propyl and phenylrespectively. Photolysis of these pyrazolino compounds in the mannerdescribed above yielded 16u,17a-(1'-ethylmethylene)-, 16a,17a(1',1'-dimethylmethylene)-, 16a, 17a (1'-n-propylmethylene)-,16a,17u-(1',1'-spirocyclopropylmethylene)- and 1611,1713(1'-phenylmethylene)- pregn-4-en-11fi,21-di01-3,20 dione 21-acetaterespectively.

EXAMPLE XIX In a manner described under Example VIII 9a-fluoropregn4,16-diene-11fl,21-diol-3,20-dione 21-acetate was condensed withdiazo-ethane, l-diazo-propane, 2-diazopropane-diazo-n-butane,diazo-cyclo-propane and phenyldiazomethane to give the pyrazolinocompounds substituted in the methylene group by 3'-methyl-, 3'-ethyl,3',3'- dimethyl, 3-n-propyl, 3',3'-spirocyclopropyl and 3'-phenylrespectively.

Photolysis of these substituted pyrazolino compounds as described inExample VIII yielded the 16ot,17vt-(1'- methylmethylene)-, 1611,1703(1'-ethylmethylene), 160:, 17a (1,1' dimethyl-methylene)-,16a,17a-(1-propylmethylene 16oz, 17w 1', 1'-spirocyclopropyhnethylene)and 1611,1704- 1'-phenylmethylene) -9a-fiuoro-pregn-4-ene-11fl,21-diol-3,20-dione 21-acetate respectively.

In a similar manner 6a-methyl, 6a-fluoro-pregna-4,16-diene-l1;9,21-dio1-3,20-dione 21-acetate have been condensed withdiazo-ethane, l-diazo-propane, 2-diazo-propane, diazo-n-butane,diazo-cyclopropane and phenyldiazomethane to give the substitutedpyrazolino compounds.

Photolysis in the manner described gave 16a,17amethylene pregn-4-ene-118,21-diol-3,20-dione 21-acetate substituted in the 16a,17a-methylenegroup by either methyl, ethyl, n-propyl, dimethyl, spirocyclo-propyl orphenyl as in position 6a by either methyl, chloro or fluoro.

EXAMPLE XX In a manner described under Example VIII pregna- 4,9(11),16-trien-21-ol-3,20-dione acetate was condensed with diazo-ethane,l-diazo-propane, 2-diazopropane, diazobutane, diazocyclopropane andphenyl-diazomethane to give the pyrazolino compounds substituted in themethylene group by 3'-methyl-, 3'-ethyl-, 3',3'-dimethyl, 3-n-propyl,3',3'-spirocyclopropyl and 3'-phenyl respectively.

Photolysis of a 1% solution in dioxan of the above pyrazolino compoundyielded the corresponding 16a,17o-

(1' methylmethylene)-, 16a,17a (1'-ethylmethylene)-, 16a,17a(1',1'-dimethylmethylene)-, 16a,17 x-(1'-n-propylmethylene 16a,17a-(1',1'-spirocyclo-propyl-methylene) and 16a, 17a-1'-phenylmethylene)-pregna-4,9 1 1 diene-21-ol-3,20-dione acetate,respectively.

EXAMPLE XXI 1604,1170: 3,1 (3 methyl 1' pyrazolino) pregna-4,9(11)-dien-2l-ol-3,20-dione acetate (1.8 g.) was dissolved in peroxidefree dioxan (100 ml.) and water (20 m1.) and treated withN-bromoacetamide (0.84 g.; 1.3 moles) and a few drops of perchloric acidThe solution was stirred for mins. and then a saturated solution ofsodium bisulphite added to destroy excess bromoacetamide. After additionof chloride, the extract was washed with dilute sodium bicarbonatesolution and then water, dried and evaporated under reduced pressure togive 16ot,17a-(3-methyl-1'-pyrazolino) 9abromopregn-4-ene-11fl,21-diol-3,20-dione 21-acetate (2.1 g.). Thisproduct was dissolved in methanol (200 ml.) and potassium acetate (5.5g.) added and the solution boiled under reflux for 3 hours, thenconcentrated under reduced pressure and the product precipitated by theaddition of water. Recrystallisation from acetone/hexane gave pure9,8,11,B-oxido-16a,17u-3',1-(3'-methyl 1'pyrazolino)-pregn-4-en-21-ol-3,20-dione acetate (1.1 g.).

The foregoing 96,11,6-oxido-16a,Not-pyrazolino compound (1.0 g.) indioxan (50 ml.) was irradiated in a quartz flask by means of a mediumpressure mercury vapour lamp situated 6 cm. away for 45 mins. The dioxanwas then distilled off under reduced pressure and the residuecrystallised from methanol to yield 913,115-0xido-16a,17a-(1'-methylmethylene)-pregn 4 en 21 ol-3,20- dione acetate (0.6g.).

The foregoing compound (0.6 g.) was dissolved in methylene chloride (4ml.) and added to a solution of anhydrous hydrofluoric acid (1.2 ml.) intetrahydrofuran (2.3 ml.) and methylene chloride (0.8 ml.) at --60 C.The solution was then allowed to warm up to 5 C. and maintained therefor 3 /2 hours, and then washed in an excess of saturated sodiumbicarbonate solution with more methylene chloride. The methylenechloride layer was separated, washed with water, dried and evaporatedunder reduced pressure. The residue was dissolved in benzene/hexane andchromatographed on silica gel, removal of the solvent andrecrystallisation from aqueous methanol gave9u-fluoro-16a,17u-(1'-methylmethylene)-pregna-4-ene-11,3,21-dio1-3,20-dione 21-acetate (0.4 g.).

In a similar manner 16a,17a-(1-ethylmethylene)-,16a,17u-(1'-n-propylmethylene)-, 16a, 17u-( l,1-dimethyl methylene)-,16a,17a-(1,1'-spirocyclomethylene)- and16a,17a-(1'-phenylmethylene)-9u-fluoro pregna 4 ene-1l/3,21-diol-3,20-dione 2l-acetate were prepared.

EXAMPLE XXII A solution of 16a,17a-(1'-methylmethylene)-21-hydroxy-A-pregnatrien-3,20-dione acetate (3.53 g.) in dimethylformamide (21.2cc.) was reacted with 70% perchloric acid (0.6 cc.) andN-bromo-succinimide in the absence of light as described in a previousexample. The reaction furnished 9a-bromo-115,21-dihydroxy-16a,17a- (1'methylmethylene) A pregnadiene-3,20-dione 11- formate 21-acetate (4.24g.); M.P. 160-166 C.; [0:1 +159 (C, 0.5 in chloroform).

9a-bromo 115,21 dihydroxy 16a,17x (1' methylmethylene) Apregnadiene-3,20-dione ll-formate 21- acetate (4.24 g.) intetrahydrofuran (35 cc.) and methanol (44 cc.) was treated with asolution of sodium (0.268 g.) in methanol (10.6 cc.) at 15 C., asdescribed in a previous example, to give 9/3,11;3-oxido-16a,17a-(1'-methylmethylene) 21 hydroxy A pregnadiene-3,20- dione (2.37 g.); M.P.166-168 C.; [a] (C, 0.95 in chloroform).

A solution of 93,11,9-oxido-16a,17a-(1'-methylmethylene)-2l-hydroxy-A-pregnadiene-3,20-dione (1.54 g.) in pure chloroform (8.6 cc.) was addedto anhydrous fluoride (4.16 g.) in pure chloroform (2.88 cc.) andtetrahydrofuran (6.4 cc.) at --60" C. and washed in with chloroform (8cc.). After one hour at 0 C. and 0.5 hours at 15 C, the product wasisolated exactly as described in a previous example to give9a-fiuoro-1lfi,21-dihydroxy- :,17a (1 methylmethylene) Apregnadiene-3,20- dione (1.5 g.); M.P. 224230 C.; [111 +154 (C, 0.95 inchloroform); A (in ethanol) 240 m (6 17,400).

EXAMPLE XXIII Treatment of 9a-fiuoro-11,8,21-dihydroxy-16a,17m-(1-vinylmethylene)-A -pregnen-3,20-dione 21-acetate (2 g.) in boilingbenzene (2 0 cc.) and acetic acid (2 cc.) withdichlorodicyanobenzoquinone (1.81 g.) for 15 hours and hydrolysis of theproduct with 1.1 mole equivalents of sodium hydroxide in aqueousmethanol furnished 9afluoro-1lfl,21-dihydroxy 160:,1701. (1'vinylmethylene)- A -pregnadiene-3,2O-dione (1.4 g.), A (in ethanol) 240my. (6 17,100).

1 1 We claim: 1. 16,17-substituted steroids having the formula:

wherein C -C and C -C are selected from the group consisting of asaturated and an unsaturated bond,

Y is selected from the group consisting of H(OH) and keto,

W is selected from the group consisting of hydrogen and halogen,

Z is selected from the group consisting of hydrogen,

methyl and halogen,

R is selected from the group consisting of hydrogen,

hydroxyl, acyloxy and halogen, wherein acyloxy is derived from an acidselected from the group consisting of an inorganic acid and an organiccarboxylic acid having 1-18 carbon atoms,

X is selected from the group consisting of hydrogen,

lower alkyl, alkenyl, alkynyl, and phenyl,

X is Selected from the group consisting of lower alkyl,

alkenyl and alkynyl,

X +X form together with the methylene carbon atom a lower cycloaliphaticgroup.

wherein C C is selected from the group consisting of a saturated and anunsaturated bond,

Y is selected from the group consisting of H(BOH) and keto,

W is selected from the group consisting of hydrogen and fluoro,

Z is selected from the group consisting of hydrogen,

methyl, chloro, and fiuoro,

R is selected from the group consisting of hydrogen and acyl derivedfrom an organic carboxylic acid having 1-18 carbon atoms,

P is hydrogen, and

P is selected from the group consisting of lower alkyl having 1 to 6carbon atoms, alkenyl and alkynyl.

References Cited UNITED STATES PATENTS 3,418,316 12/1968 Taub et al260239.5

ELBERT L. ROBERTS, Primary Examiner US. Cl. X.R. 260-2395, 239.55

